Project Summary The objective of this proposal is to design new agents that release biological effectors in the presence of hydrogen peroxide, providing an approach to spatially precise strategies for treating a multitude of medical conditions that are characterized by oxidative stress. These conditions include, but are not limited to, reperfusion injury, viral infection, neurodegeneration, traumatic brain injury, and cancer. Spatially precise release will be beneficial because it can minimize general drug exposure, allowing for lower doses while mitigating side effects. The new agents are based on the hydrogen peroxide mediated conversion of ?-boryl ethers and related structures to hemiacetals, leading to a breakdown that forms a ketone and releases the effector. The ketone by-products that are released in this approach are non-toxic, providing excellent opportunities to treat diseases in which the promotion of cellular responses, rather than cell death, is the objective. This multidisciplinary program will utilize organic synthesis, kinetics studies, cellular assays, and animal studies to achieve its objectives. The first Specific Aim is to devise agents that release cyclic dinucleotides under oxidative conditions in an effort to stimulate an immune response against tumors. The second Specific Aim is to merge drug release with radiation therapy to create a site-specific approach to cancer treatment. Releasing agents that mimic the physiological response to radiation will allow for an autoinductive release mechanism that lowers the required radiation dose and minimizes late stage side effects. The combination of the skills of the PIs and collaborators on these projects creates unique opportunities for localized disease treatment while providing guidance for developing a general strategy for designing prodrugs that release structurally disparate agents.